tbuckley/cabot-search huggingface dataset:
P1322: EFFECTS OF DONOR-SPECIFIC ANTI-HLA ANTIBODIES (DSA) FOR PRIMARY GRAFT FAILURE OF HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THALASSEMIA MAJOR
Authors: Jianyun Liao, Chaoke Pu, Lan He, Jujian He, Weiwei Zhang, Yuqian Xia, Yuelin He, Chunfu LI
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: Donor-specific anti-HLA antibodies (DSA) have been recently recognized as an important barrier against successful engraftment of donor cells, which can affect transplant survival. Aims: To investigate the effects of donor-specific anti-HLA antibody (DSA) for primary graft failure(GR) of haploidentical hematopoietic stem cell transplantation(HSCT) in thalassemia major and viable treatment for DSA. Methods: HLA antibodies were examined using the Luminex-based single Ag assay for 196 patients with thalassemia major who underwent HSCT from January 2018 to December 2022 in our center, and the correlations of GR and DSA were also analyzed. Of the total 196 patients, sixty (30.6%) patients were tested for antibodies corresponding to donor HLA Ags (DSA positive). All the 60 patients were going plasmapheresis, platelet transfusion, buffy coat depletion and antibody neutralization, and were administered with rituximab, bortezomib, fodarabine and dexamethasone, grouped by different levels of the median fluorescence intensity (MFI): A. 5 patients in High DSA group (MFI > 10000); B. 13 patients in Median DSA group (MFI 5000-10000); C. 42 patients in low DSA group. The correlation between MFI, nucleated cells and CD34 count with engraftment was analyzed. Results: The 136 patients with a test of negative DSA had no primary GR. Among 60 DSA positive patients, 3 patients (Group A) had primary GR. Multivariate analysis showed that DSA was an important hindrance against successful engraftment of donor cells [OR=12.17(95%CI 1.205-122.812), P =0.034]. GR occurred in 3 of 18 patients with high and median DSA (MFI>5000), and there was no GR in 42 patients with low DSA (MFI 500-4999). The difference between the two groups was statistically significant [P =0.024]. The average number of nucleated cells (108/kg) in group A and B was 22 and 23, and the average CD34 count (106/kg) was 8.97 and 18.54. Conclusion: Post-transplant testing and treatment for patients with DSA are crucial for successful engraftment. GR occurs more likely in the condition of median or higher DSA(MFI > 5000), under which the CD34 counts (106/kg) of the transfusion dosage of donor cells reach above 20 is recommended. Keywords: Thalassemia, Donor, Haploidentical stem cell transplantation
P349: CRISPR/CAS9 SCREEN IDENTIFIES PTPMT1 AS AN ESSENTIAL GENE FOR ACUTE LYMPHOBLASTIC LEUKEMIA PROLIFERATION
Authors: Jiazheng LI, Lihua Lu, Luting Luo, Lingyan Wang, Jianda Hu
Journal: HemaSphere (2023)

Background: The overall survival of acute lymphoblastic leukemia (ALL) remains poor. A genome-wide CRISPR/Cas9 screen is helpful to identify essential genes in ALL. Aims: Our goal is using CRISPR/Cas9 screen to identify gene related proliferation in ALL. And PTPMT1 knockout Jurkat and Nalm6 cells were used to further explore biological function and mechanisms. Methods: CRISPR/Cas9 screen in ALL cell line Jurkat cells for high-throughput sequencing was used to identify genes related proliferation. The expression levels and prognostic values of protein-tyrosine phosphatase mitochondrial 1 (PTPMT1) were investigated using GSE13159 dataset, TARGET ALL P2 dataset and our clinical sample. The function of PTPMT1 on cell proliferation, cell cycle, lipid reactive oxygen species(L-ROS), mitochondrial morphology was further explored in ALL cell line Jurkat and Nalm6. Functional enrichment analyses were performed on differentially expressed genes identified from PTPMT1 expression groups within the GSE66002 dataset. Results: PTPMT1 was in the top of 5 ranks for twice screen which ranked by P value. The expression of PTPMT1 was significantly higher, and correlated with poor progression free survival (P<0.0001) and overall survival (P<0.0001) in ALL patients. Knockout of PTPMT1 not only attributed to mitochondrial damage, slower cell proliferation, and G1 phase arrest, but also promoted RSL3-induced L-ROS increased. By analyzing GSE66002 dataset, we found that the majority of GO terms and KEGG pathway were associated with ROS. Further experiments found that downregulation or upregulation of PTPMT1 decreased or increased the protein expression of NRF2, KEAP1, HO-1. Summary/Conclusion: PTPMT1 was identified as an important gene related proliferation in ALL by CRISPR/cas9 screen. And PTPMT1 promoted cell proliferation and RSL3- induced ferroptosis by NRF2/ KEAP1/ HO-1 pathway. Keywords: Acute myeloid leukemia, ALL, Proliferation
P1645: IMPACT OF VON WILLEBRAND FACTOR AND ADAMTS13 ON CARDIOVASCULAR COMPLICATIONS AND BLEEDING IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION AND NORMAL SINUS RHYTHM CONTROLS: 10 YEARS FOLLOW UP.
Authors: Waldemar Wysokinski, Danielle Vlazny, Robert Mcbane, Naser Ammash, Damon Houghton, Matylda Mazur, Ana Casanegra, Jozef Mruk, Diane Grill, Joshua Slusser, Rowlens Melduni
Journal: HemaSphere (2023)

Topic: 34. Thrombosis and vascular biology - Biology & Translational Research Background: Increasing Von Willebrand factor (VWF) correlates with the development of left atrial blood stasis in non-valvular atrial fibrillation (NVAF). However, the long-term impact of elevated VWF relative to ADAMTS13 activity level, its key regulator, is not well established in patients NVAF. Aims: To assess the long-term impact of VWF and ADAMTS13 activity levels on clinical outcomes of patients with NVAF and normal sinus rhythm controls. Methods: Baseline VWF antigen, VWF activity, ADAMTS13 activity, and echocardiographic measures were obtained for all subjects. Adverse cardiovascular events, major bleeding, clinically relevant non-major bleeding (CRNMB), and all-cause mortality were assessed by clinical follow-up, questionnaire, or telephone communication. Results: During 10 years of follow-up, there were 7 strokes, 2 TIA, 10 other thromboembolic events and 96 deaths in NVAF group compared to 2 TIA events, 4 systemic emboli and 30 deaths in NSR control group. In general, there were more adverse cardiovascular events in NVAF compared to NSR groups (p=0.022, see Figure). Major bleeding and CRNMB happened in 21 and 45 in NVAF and 1 and 12 in NSR patients. VWF antigen concentration and activity were an independent predictor of all-cause mortality (HR: 1.011, 95%CI: 1.008, 1.014, p<0.0001, and HR 1.010 (95%Cl:1.007,1.013, p<0.001) while lower activity of ADAMTS13 was associated with better survival ((HR 0.992, 95%CI 0.987, 0.996, P=0.0004). Presence of left atrial appendage thrombus, spontaneous echo contrast, low left atrial appendage emptying velocity, and increased left atrium volume index were not associated with adverse cardiovascular events or bleeding in NVAF patients. Summary/Conclusion: Higher level of VWF at baseline predicted a higher risk of death while lower activity of its key regulator ADAMTS13, was associated with better survival in NVAF and NSR patients.Keywords: ADAMTS13, Thromboembolism, von Willebrand factor (vWF), Bleeding
P1500: WHAT’S DRIVING RDW? IN-VITRO AND IN-SILICO EVIDENCE FOR OXIDATIVE STRESS
Authors: Huibert-Jan Joosse, Brigitte van Oirschot, Sander A.A. Kooijmans, Imo E Hoefer, Richard A.H. Van Wijk, Albert Huisman, Wouter W Van Solinge, Saskia Haitjema
Journal: HemaSphere (2023)

Topic: 29. Iron metabolism, deficiency and overload Background: Red blood cell distribution width (RDW) is a biomarker associated with a variety of clinical outcomes. While anemia and subclinical inflammation have been posed as underlying pathophysiology, it is unclear what mechanisms underlie these associations. Aims: We aimed to unravel the mechanisms in silico by using a large clinical dataset and subsequently validate our findings in vitro. Methods: We retrieved complete blood counts (CBC) from 1,403,663 blood samples from the Utrecht Patient Oriented Database as measured on the Abbott CellDyn Sapphire, in order to model RDW by using gradient boosting regression (XGBoost) with different sets of predictors: one set with all variables (set 1), one set without percentage microcytic (pMIC) and macrocytic erythrocytes (pMAC) and mean corpuscular volume (MCV) (set 2), and one set without these variables and reticulocyte-related variables (set 3). We performed analyses in patients with and without anemia, in men and women, and in patients younger and older than 50. Additionally, we validated our model using data from the Abbott Allinity (n = 70) and data from the Abbott CellDyn Sapphire as measured in primary and secondary care (n = 513,564). We then validated our hypothesis regarding oxidative stress using an in vitro approach, where we induced blood samples with oxidative stress. Additionally, we measured erythrocyte deformability, by using Laser Optical Rotational Red Cell Analyzer techniques, and vesiculation. Results: Only pMIC and macrocytic pMAC erythrocytes and MCV were most important in modelling RDW (RMSE=0.40, R2=0.96), considering removing the variables in sets 2 (RMSE=1.00, R2=0.76) and 3 (RMSE=1.34, R2=0.57) resulted in significantly worse performance. Subgroup analyses showed similar performance pattern, and validation in both Allinity data (RMSE=0.75, R2=0.87) and primary and secondary care data (RMSE=0.45, R2=0.94) confirmed the generalizability of the model as built on set 1. Our In vitro result after induction of oxidative stress underscored our results, as we observed an increased RDW and decreased erythrocyte volume, as well as increased pMIC, yet no vesiculation was observed. Furthermore, we found that deformability decreased as a result of oxidative stress possibly affecting sphericity of erythrocytes. Summary/Conclusion: We found that erythrocyte size, especially pMIC, is most informative in modelling RDW, but no role for anemia or chronic subclinical inflammation. Furthermore, oxidative stress may affect deformability of erythrocytes, and may therefore play a role in the association between RDW and clinical outcomes.Keywords: Red blood cell, Erythrocyte, Machine learning
P1055: BROMODOMAIN AND EXTRA-TERMINAL (BET) INHIBITOR INCB057643 (LIMBER-103) IN PATIENTS (PTS) WITH RELAPSED OR REFRACTORY MYELOFIBROSIS (R/R MF) AND OTHER ADVANCED MYELOID NEOPLASMS: A PHASE 1 STUDY
Authors: Justin M. Watts, Anthony M. Hunter, Alessandra Iurlo, Blanca Xicoy, Francesca Palandri, Brandi Reeves, Alessandro Vannucchi, Prithviraj Bose, Rosa Ayala Diaz, Anna B. Halpern, Xuejun Chen, Francis Seguy, Feng Zhou, Fred Zheng, Pankit Vachhani
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: BET proteins are epigenetic readers that regulate expression of critical oncoproteins involved in the pathophysiology of hematologic malignancies, including MF. INCB057643 is a small-molecule BET inhibitor evaluated as monotherapy and in combination with ruxolitinib (RUX) in pts with advanced malignancies in 2 previous phase 1/2 clinical trials. Aims: To evaluate the safety and tolerability of INCB057643 in pts with R/R MF and other advanced myeloid neoplasms. Methods: In this ongoing phase 1, 3 + 3 dose-escalation/expansion study (NCT04279847), pts aged ≥18 years received INCB057643 (4 mg once daily [qd]; escalation up to 12 mg qd) as (1) monotherapy (part 1) in R/R MF, myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes (MDS/MPN) or (2) added to RUX (part 2) in pts with MF and suboptimal response to RUX. The primary endpoint is safety and tolerability, including identification of dose-limiting toxicities (DLTs). Results: 13 pts have been treated in part 1 (4 mg, n=6; 8 mg, n=4; 10 mg, n=1; 12 mg, n=2), and 3 pts received 4 mg + RUX in part 2 (overall age range, 50–79 years; men, n=9; study treatment duration range, 15–314 days). 12 pts had MF, and 4 had MDS/MPN. All 6 pts in the 4-mg cohort discontinued treatment (3 for progressive disease [PD]; MF, n=2; MDS/MPN, n=1); 1 pt with MF in the 12-mg cohort discontinued for thrombocytopenia. The other 9 pts remain on treatment. Thrombocytopenia was the most common treatment-emergent adverse event (TEAE; n=9; Table) and the only TEAE leading to discontinuation (n=3). Grade ≥3 TEAEs occurring in ≥1 pt were thrombocytopenia (n=4), anemia (n=3), and hypokalemia (n=2). There were 8 serious AEs across 4 pts, with only COVID-19 occurring in >1 pt (n=2); all but one (pneumonia) were considered unrelated to study treatment. There were 2 DLTs (thrombocytopenia [MDS/MPN pt] and hyperbilirubinemia [MF pt]; both 12-mg cohort) and 2 deaths (both 4-mg cohort due to PD [MF, n=1; MDS/MPN, n=1]). Summary/Conclusion: Treatment with INCB057643 monotherapy (4 and 8 mg qd) and in combination (4 mg qd) with RUX was generally well tolerated in this pt population. The 12-mg qd monotherapy dose was not tolerated and caused 2 DLTs. There were no treatment-related fatal events. Dose finding in part 1 is ongoing with 10 mg qd, after which a recommended phase 2 dose will be declared. Combination dose escalation is also ongoing. Preliminary efficacy including spleen size and symptoms will be available for presentation. Keywords: Myelofibrosis, Myeloproliferative disorder, Myelodysplastic syndrome, Epigenetic
P392: FEATURES AND TREATMENT OF PATIENTS WITH T(8;14)(Q24;Q11)/ TCRA/D::MYC TRANSLOCATED T ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOMA (T-ALL/LBL)
Authors: Xian Zhang, Tong Wang, Yang Zhang, Fang Wang, Jiaqi Chen, Jingbo Ni, Ruijuan Sun, Zhijie Wei, Gailing Zhang, Wenqian LI, Jingjing LI, Peihua Lu
Journal: HemaSphere (2023)

Background: Patients with t(8;14)(q24;q11)/ TCRA/D::MYC-translocated T acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) are a rare subgroup of T-ALL/LBL associated with induction failure and aggressive disease. But recently, we found that this type is not uncommon in refractory and relapsing T ALL. Aims: We hope to find the commonality of this kind of disease and explore effective treatment methods. Methods: All T-ALL/LBL patients were confirmed by comprehensive diagnosis of cytomorphology, immunophenotype, cytogenetics and molecular biology. The CD7 Chimeric Antigen Receptor T-Cell (CAR-T) therapy clinical trial for T-LBL/ALL patients was initiated October 2020 (NCT04916860). Results: We conducted a retrospective analysis of 14 patients with the t(8;14) translocation, who were all detected in refractory or relapsed patients. Five had the t(8;14) (q24.1;q11.2) in their primary tumor, and 9 at the time of relapse. Extramedullary invasion occurred in 9/12 patients. Four patients had a STIL::TAL1 translocation, 6 had a PTEN mutation, and 6 had CDKN2A/B gene loss. Seven patients who only received chemotherapy or allogeneic hematopoietic stem transplantation (HSCT) all died. The median overall survival (OS) was only 3 months (range: 2-7 months). Since the CD7 CAR-T therapy was used for refractory or relapsed T-ALL/LBL from Oct, 2020, 6 patients were treated with the CD7 CAR-T therapy and 5 achieved CR on Day 30. Three patients achieved minimal residual disease (MRD) negative status and two subsequently became MRD-positive. Four patients who bridged to HSCT after CAR-T have remained disease-free to date. Summary/Conclusion: The prognosis of the patients with t(8;14)/ TCRA/D::MYC-translocated T-ALL/LBL was very poor, we should pay enough attention to it. while CD7 CAR-T allows patients to achieve short-term CR. Allo-HSCT after CAR-T therapy should be considered for long survival. Table 1. Characteristic of the 14 T-ALL/LBL patients harboring the t(8;14)(q24;q11) translocation - Characteristic Value Gender (M/F) 10/4 Age Median (range) — yr 15 (2-35) 2-14yr 6 15-61yr 8 With EMD — No. CNSL 6/12 Diffused EMD 3/12 With other fusion gene 5 STIL::TAL1 4 MLL-PTD 1 Complex cytogenetic 10/12 Additional gene mutations PTEN/PTPN 6 NOTCH1 2 CCND3 3 TP53 1 CDKN2A/B deletion 6/14 Disease status — No. Refractory (3 median chemotherapy courses) 5 Relapsed (10 median chemotherapy courses) 9 Transplantation status — No. Yes 5 No 9 CD7 CAR-T therapy status — No. Yes 6 No 8 EMD: extramedullary disease. CNSL: central nervous system leukemia. CART: Chimeric Antigen Receptor T-Cell. Keywords: Lymphoma, T cell acute lymphoblastic leukemia
P955: BURDEN OF INFECTION IN PATIENTS WITH MULTIPLE MYELOMA AND SECONDARY IMMUNODEFICIENCIES: A RETROSPECTIVE COHORT STUDY
Authors: Joshua Richter, Colin Anderson-Smits, Kaili Ren, Marta Kamieniak, Drishti Shah, Csaba Siffel
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: In patients with multiple myeloma (MM), both the underlying disease and immunosuppressive therapy can result in many patients developing secondary immunodeficiency disease (SID). Patients with MM and SID are at high risk of bacterial and viral infections. Aims: This study aimed to provide insights into the burden of infection in patients with MM with or without SID. Methods: In this retrospective cohort study, data were extracted from the Optum-Humedica electronic record database during the period October 1, 2015, to March 10, 2020, which included a 6-month pre-index period (PIP) and 12-month follow-up following patient identification. Patients aged ≥ 18 years with a confirmed diagnosis of MM in the PIP were included in the analysis and stratified into two cohorts: those with (SID cohort) and those without SID (no-SID cohort). If a patient had SID or primary immunodeficiency disease in the PIP, they were excluded. The first occurrence of a hypogammaglobulinemia International Classification of Diseases, Tenth Revision, code, or a low (< 5.0 g/L) serum immunoglobulin G level was defined as the SID index date. Results: Of patients with MM, 870 with SID and 3768 without SID were included (mean age: 66.5 and 68.7 years; males: 54.3% and 53.6%; respectively). At 12-month follow-up, significantly more patients in the SID cohort experienced ≥ 1 infection than the no-SID cohort (58.9% vs 32.1%, p < 0.001). A similar pattern was observed for mean number of infections, patients experiencing ≥ 1 severe bacterial infection or ≥ 1 infection-associated hospitalization (Table). The most common infection in both cohorts was bacterial: SID, mean (standard deviation) number of bacterial infections 6.83 (8.04) and no-SID, 4.73 (6.57), p < 0.001. Kaplan–Meier analysis showed overall survival at 24 months was lower in the SID cohort (74.9% of patients alive) than the no-SID cohort (81.8%). Summary/Conclusion: Patients with MM and SID have a substantially higher burden of infection and healthcare resource use, and lower overall survival than those without SID. Understanding this burden will allow for earlier targeted treatment of individuals at risk of SID. This abstract was previously presented at the European Society for Medical Oncology (ESMO) 2022 Congress. Takeda Development Center Americas, Inc. funded this study. Takeda Pharmaceuticals International AG funded writing support.Keywords: Immunodeficiency, Multiple myeloma, Secondary, Infection
P1275: SAFETY AND EFFICACY OF HUMAN AMNIOTIC EPITHELIAL STEM CELLS EYE DROP IN OCULAR CHRONIC GRAFT-VERSUS-HOST DISEASE
Authors: Xianjing Cheng, Ruihao Huang, Wei Fan, Yuancheng Zhao, Shiqin Huang, Rongdi Yuan, Xiaoqi Wang, XI Zhang
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: Around 50% of patients suffer from ocular chronic GVHD (ocGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which causes serious dryness and visual impairment. Nevertheless, the current clinical therapies for ocGVHD including artificial tears, immunosuppression therapy, or punctual occlusion usually provide limited benefits. Amniotic membrane transplantation (AMT) can significantly alleviate ocular symptoms in ocGVHD patients, but AMT is an invasive surgery and is not applicable to all patients with ocGVHD. Therefore, we designed a clinical trial to demonstrate the safety and efficacy of human amniotic epithelial stem cells (hAESC) eye drops in ocGVHD. Aims: To investigate the safety and efficacy of hAESC therapy for ocGVHD in patients undergoing allo-HSCT. Methods: Register Number: ChiCTR2200057857. The enrolled eyes received 1*106 cells/mL of hAESC eye drops four times a day for a period of one to three cycles of treatment (A cycle was defined as two weeks of continuous administration and two weeks without hAESC eye drops). Additionally, the side effects or adverse events relevant to the topical application of the hAESC eye drops would be recorded during the follow-up. The primary endpoint is the ocular surface disease index (OSDI) score after treatment with hAESC eye drops. Results: A total of 17 post-allo-HSCT ocGVHD patients (39±11y; range 21-56y) involving 34 eyes were enrolled. After treatment with hAESC eye drops, 82.35% of ocGVHD patients demonstrated a significant reduction in OSDI score (P=0.0009). There was also a statistical improvement in Schirmer basal secretion score (P=0.0353), corneal fluorescein staining score (P<0.0001), and fluorescein tear breakup time (P=0.0268). No adverse events associated with hAESC were observed. The results revealed that hAESC eye drops ameliorated ocular symptoms, increased tear secretion, and improved corneal epithelial recovery of ocGVHD. Conclusion: The study suggested that hAESC eye drop is a safe and efficient therapy for ocGVHD patients. Keywords: Chronic graft-versus-host